Biaryl diazabicycloalkane amides as nicotinic acetylcholine agonists

ABSTRACT

Acetylcholine receptor ligands of formula I  
                 
 
wherein A, D, Ar 1 , E and Ar 2  are as described in the specification, diastereoisomers, enantiomers, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

TECHNICAL FIELD

This invention relates to diazabicycloalkane amides orpharmaceutically-acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy.The invention also relates to compounds that are ligands for nicotinicacetylcholine receptors (nAChRs).

BACKGROUND OF THE INVENTION

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, anxiety,depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors:Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in AnnualReports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc.,San Diego, Calif.; and in Williams et al. (1994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

DISCLOSURE OF THE INVENTION

We have invented compounds of formula I:

wherein:

-   -   A is a moiety of formula II:    -   D is oxygen or sulfur;    -   E is a single bond, oxygen, sulfur, or NR³;    -   Ar¹ is a 5- or 6-membered aromatic heterocyclic ring having 1, 2        or 3 heteroatoms selected from nitrogen, oxygen or sulfur where        not more than one of said heteroatoms is oxygen or sulfur, or    -   Ar¹ is phenyl;    -   Ar² is a 5- or 6-membered aromatic heterocyclic ring having 1, 2        or 3 heteroatoms selected from nitrogen, oxygen or sulfur where        not more than one of said heteroatoms is oxygen or sulfur, or    -   Ar² is phenyl, or    -   Ar² is an 8- or 9-, or 10-membered fused aromatic carbocyclic        ring or fused aromatic heterocyclic ring having 1, 2 or 3        heteroatoms selected from nitrogen, oxygen or sulfur where not        more than one of said heteroatoms is oxygen or sulfur, or an 8-        or 9-, or 10-membered aromatic carbocyclic ring;    -   the rings Ar¹ and Ar² are substituted with 0, 1, 2 or 3        substituents selected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl,        C₂₋₄alkynyl, CN, NO₂, CF₃NR¹R², CH₂NR¹R², OR², CH₂OR² or CO₂R³;    -   R¹ and R² at each occurrence are independently selected from        hydrogen, C₁₋₄alkyl, aryl, heteroaryl, C(O)R³, C(O)NHR³, CO₂R³        or SO₂R³, or    -   R¹ and R² in combination is —(CH₂)_(j)G(CH₂)_(k)— wherein G is        oxygen, sulfur, NR³, or a bond;    -   a, b and c are each 1 or 2;    -   j is 2, 3 or 4;    -   k is 0, 1 or 2, and    -   R³ at each occurrence is independently selected from hydrogen,        C₁₋₄alkyl, aryl, or heteroaryl;        or a diastereoisomer, enantiomer or pharmaceutically-acceptable        salt thereof.

One embodiment of the invention comprises compounds wherein D is oxygen.

Another embodiment of the invention comprises compounds wherein E is asingle bond.

Yet another embodiment of the invention comprises compounds wherein E isoxygen or NR³.

A particular embodiment of the invention comprises compounds wherein Ais

or a diastereoisomer, enantiomer or pharmaceutically-acceptable saltthereof.

Particular compounds of the invention are those wherein Ar¹ is a 5- or6-membered aromatic heterocyclic ring having 1 or 2 heteroatoms selectedfrom nitrogen, oxygen or sulfur where not more than one of saidheteroatoms is oxygen or sulfur, or Ar¹ is phenyl.

Particular compounds of the invention are also those wherein Ar¹ is abenzene ring, furan ring or thiophene ring.

Particular compounds of the invention are also those wherein Ar² is a 5-or 6-membered aromatic heterocyclic ring having 1 or 2 heteroatomsselected from nitrogen, oxygen or sulfur where not more than one of saidheteroatoms is oxygen or sulfur, or a phenyl.

Particular compounds of the invention are also those wherein Ar² is abenzene ring, furan ring, thiophene ring, or pyridine ring.

Particular compounds of the invention are also those wherein the -EAr²and the C(=D)A moieties on Ar¹ are positioned in a 1,3-relationshiprelative to each other.

Particular compounds of the invention are also those wherein Ar¹ or Ar²is substituted with 0 or 1 substituents selected from: halogen,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR³,CH₂OR³, CO₂R³, and CF₃.

Particular compounds of the invention are also those wherein A is amoiety of formula II:

-   -   D is oxygen;    -   E is a single bond;    -   Ar¹ is a 5- or 6-membered aromatic heterocyclic ring having 1, 2        or 3 heteroatoms selected from nitrogen, oxygen or sulfur where        not more than 1 of said heteroatoms is oxygen or sulfur, or    -   Ar¹ is phenyl    -   Ar² is a 5- or 6-membered aromatic heterocyclic ring having 1, 2        or 3 heteroatoms selected from nitrogen, oxygen or sulfur where        not more than 1 of said heteroatoms is oxygen or sulfur, or    -   Ar² is phenyl,        or a diastereoisomer, enantiomer or pharmaceutically-acceptable        salt thereof.

Still more particular compounds of the invention are those wherein Ar¹is a benzene ring, furan ring or thiophene ring.

Particular compounds of the invention are also having the groups -EAr²and —C(═O)A, positioned in a 1,3-relationship relative to each other andwherein Ar² has 0 or 1 substituents selected from: halogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR¹, CH₂OR¹, CO₂R³,and CF₃.

Most particular compounds of the invention include:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-3-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(2-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(3-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(4-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-2-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-3-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-2-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-3-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(2-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(4-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-2-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-3-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-2-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-3-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-phenylthiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(2-pyridyl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(2-pyridyl)thiophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridyl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(3-pyridyl)thiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(4-pyridyl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(4-pyridyl)thiophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-2-yl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-2-yl)thiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-3-yl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-3-yl)thiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-2-yl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-2-yl)thiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-3-yl)thiophen-3-yl)methanone    otherwise named    (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-3-yl)thiophen-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-phenylfuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)furan-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)furan-2-yl)methanone,    and-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)furan-2-yl)methanone.

Other compounds of the invention are:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(2-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(4-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-2-yl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-3-yl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-2-yl)thiophen-2-yl)methanone,    and-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-3-yl)thiophen-2-yl)methanone.

Yet other compounds of the invention are:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-phenylfuran-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(2-pyridyl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(3-pyridyl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(4-pyridyl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-2-yl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-3-yl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-2-yl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-3-yl)furan-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-phenylthiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)thiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)thiophen-2-yl)methanone,    and-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)thiophen-2-yl)methanone.

All embodiments and particular forms of the invention encompass allenantiomers, diastereoisomers and pharmaceutically-acceptablederivatives and salts of compounds thereof.

Compounds of the invention are potent ligands for nicotinicacetylcholine receptors.

Pharmaceutically-acceptable derivatives include solvates and salts. Forexample, the compounds of formula I can form acid addition salts withacids, such as the conventional pharmaceutically-acceptable acids, forexample, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.

Compounds of the invention are useful in the treatment or prophylaxis ofhuman diseases or conditions in which activation of the α7 nicotinicreceptor is beneficial as well as in the treatment or prophylaxis ofpsychotic disorders or intellectual impairment disorders. Examples ofsuch conditions, diseases or disorders are Alzheimers disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder, Anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotinic addictionincluding that resulting from exposure to products containing nicotine,pain, for ulcerative colitis and irritable bowel disease.

As used herein, unless otherwise indicated, “C₁₋₄alkyl” includes but isnot limited to methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl,t-butyl, s-butyl moieties, whether alone or part of another group,C₁₋₄alkyl groups may be straight-chained or branched, and C₃₋₄ alkylgroups include the cyclic alkyl moieties cyclopropyl and cyclobutyl.Alkyl groups referred to herein may have 1, 2 or 3 halogen substituents.

As used herein, unless otherwise indicated, “C₂₋₄alkenyl” includes butis not limited to 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and3-butenyl.

As used herein, unless otherwise indicated, “C₂₋₄alkynyl” includes butis not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyland 3-butynyl.

As used herein, unless otherwise indicated, aryl refers to a phenyl ringwhich may have 1, 2 or 3 substituents selected from: halogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄aklyl, CN, NO₂, and CF₃.

As used herein, unless otherwise indicated, heteroaryl refers to a 5- or6-membered aromatic or heteroaromatic ring having 1, 2 or 3 heteroatomsselected from nitrogen oxygen and sulfur, provided that heteroaromaticrings contains at least one nitrogen, oxygen, or sulfur atom.

As used herein, unless otherwise indicated, halogen refers to fluorine,chlorine, bromine, or iodine.

Methods of Preparation

In the reaction schemes and text that follow, A, E, Ar¹, and Ar² unlessotherwise indicated, are as defined above for formula I.

The compounds of formula I in which E represent a single bond may beprepared according to the methods outlined in Scheme 1.

Compounds of formula I wherein D is oxygen and E is a single bond may beprepared from compounds of formula VI wherein J is a halogen or anOSO₂CF₃ substituent at the position of ring Ar¹ at which the bond toring Ar² is formed, by reaction with an appropriate organometalliccompound of formula VII in the presence of a suitable organometalliccatalyst and solvent. Suitable compounds of formula VII include boronicacids, in which M is B(OH)₂ and organotin compounds, in which M is asuitable trialkylstannyl group, for example trimethylstannyl ortri-n-butylstannyl. Suitable organometallic catalysts include palladium(0) complexes, for example tetrakis(triphenylphosphine)palladium(0) or acombination of tris(dibenzylideneacetone)dipalladium(0) and a suitabletriarylphosphine or triarylarsine ligand, for exampletriphenylphosphine, tri(o-tolyl)phosphine or triphenylarsine.

Suitable solvents include inert ether solvents, for example1,2-dimethoxyethane, tetrahydrofuran, or 1,4-dioxane, or alcohols, suchas ethanol, or mixtures thereof. If the compound of formula VII is aboronic acid, the presence of a suitable base in addition to the otherreagents is preferred. Suitable bases include sodium carbonate, cesiumcarbonate, and barium hydroxide. The reaction is carried out at atemperature of 0-120° C., and preferably at a temperature of 60-120° C.

Compounds of formula I wherein D is oxygen and E is a single bond mayalso be prepared from organometallic compounds of formula VIII byreaction with a compound of formula IX in which J is a halogen orOSO₂CF₃ in the presence of a suitable organometallic catalyst andsolvent. Suitable compounds of formula VIII include boronic acids, inwhich M is B(OH)₂ and organotin compounds, in which M is a suitabletrialkylstannyl group, for example trimethylstannyl ortri-n-butylstannyl.

Suitable organometallic catalysts include palladium (0) complexes, forexample tetrakis(triphenylphosphine)palladium (0) or a combination oftris(dibenzylideneacetone)dipalladium (0) and a suitabletriarylphosphine or triarylarsine ligand, for exampletriphenylphosphine, tri(o-tolyl)phosphine or triphenylarsine.

Suitable solvents include inert ether solvents, for example1,2-dimethoxyethane, tetrahydrofuran, or 1,4-dioxane, or alcohols, suchas ethanol, or mixtures thereof.

If the compound of formula VIII is a boronic acid, the presence of asuitable base in addition to the other reagents is preferred. Suitablebases include sodium carbonate, cesium carbonate, and barium hydroxide.The reaction is carried out at a temperature of 0-120° C., andpreferably at a temperature of 60-120° C.

Compounds of formula I wherein D is oxygen and E is a single bond mayalso be prepared from compounds of formula X by reaction with a suitablecompound of formula XI, wherein L is a suitable leaving group, using asuitable acylation procedure. Suitable leaving groups L include: OH,halogen, Oalkyl, Oaryl, OCOalkyl, OCOaryl. A suitable acylationprocedure involves treatment of a compound of formula X with a compoundof formula XI at 0-120° C. in a suitable solvent. The presence of abase, or, when Y=OH, a coupling agent, may also be necessary for thereaction to occur. Suitable bases for the reaction include:4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula I in which D is sulfur and E is a single bond maybe prepared from compounds of formula I in which D is oxygen and E is asingle bond by reaction with a suitable sulfide in a suitable solvent.The preferred sulfides are phosphorus sulfides, in particular4-methoxyphenylthionophosphine sulfide dimer (“Lawesson's Reagent”), anddiphosphorus pentasulfide. Suitable solvents for the reaction includearyl hydrocarbon solvents, for example toluene or xylene. The reactionis performed at a temperature of 0-200° C., and preferably at atemperature of 50-180° C.

Certain compounds of formula VI wherein J is halogen may be preparedfrom compounds of formula VI wherein J is hydrogen by reaction with asuitable halogenating agent in a suitable solvent. Suitable halogenatingagents include bromine. Suitable solvents include acetic acid. Thereaction is preferably performed at a temperature of 0-50° C., and mostpreferably at a temperature of 0-25° C.

Compounds of formula VI wherein J is OSO₂CF₃ may be prepared fromcompounds of formula VI wherein J is OH by reaction withtrifluoromethanesulfonic anhydride or othertrifluoromethanesulfonylating agent in the presence of a base and asuitable solvent. Suitable bases include pyridine, and2,6-di-t-butylpyridine. The reaction is preferably performed at atemperature of −78 to 120° C., and most preferably at a temperature of−78 to 0° C.

Compounds of formula VI wherein J is hydrogen, halogen, OH, or OSO₂CF₃may be prepared from compounds of formula X by reaction with a suitablecompound of formula XII, wherein L is a suitable leaving group and J ishydrogen, halogen, OH, or OSO₂CF₃, using a suitable acylation procedure.Suitable leaving groups L include: OH, halogen, Oalkyl, Oaryl, OCOalkyl,OCOaryl. A suitable acylation procedure involves treatment of a compoundof formula X with a compound of formula XII at 0-120° C. in a suitablesolvent. The presence of a base, or, when L=OH, a coupling agent, mayalso be necessary for the reaction to occur. Suitable bases for thereaction include: 4-(N,N-dimethylamino)pyridine, pyridine,triethylamine, N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when Y=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula VIII in which M is B(OH)₂ may be prepared fromcompounds of formula VI in which J is hydrogen, halogen, or OSO₂CF₃ bymethods known to one skilled in the art. For example compounds offormula VI in which J is hydrogen or halogen may be converted tocompounds of formula VIII in which M is B(OH)₂ via conversion to thecorresponding aryllithium or arylmagnesium compounds followed byreaction with trimethylborate and subsequent hydrolysis of the resultingborate ester. The reaction is performed in a suitable inert solvent, forexample, tetrahydrofuran. Alternatively, compounds of formula VI whereinJ is halogen or OSO₂CF₃ may be converted to compounds of formula VIII inwhich M is B(OH)₂ via reaction with bis(pinacolato)diboron and anorganometallic catalyst, followed by hydrolysis of the resulting borateester. For typical procedures for effecting such conversions, see, forexample, Organic Syntheses, 1963, Coll. Vol. 4, 68; J. Org. Chem. 1995,60, 7508.

Compounds of formula VIII in which M is a trialkylstannyl group may beprepared from compounds of formula VI in which J is hydrogen, halogen,or OSO₂CF₃ by methods known to one skilled in the art. For examplecompounds of formula VI in which J is hydrogen or halogen may beconverted to compounds of formula VIII in which M is a trialkylstannylgroup via conversion to the corresponding aryllithium or arylmagnesiumcompounds followed by reaction with an appropriate trialkylstannylhalide. The reaction is performed in a suitable inert solvent, forexample, tetrahydrofuran. The reaction is performed at a temperature of−78° C. to 20° C., preferably at −78° C. to 0° C. Alternatively,compounds of formula VI wherein J is halogen or OSO₂CF₃ may be convertedto compounds of formula VIII in which M is a trialkylstannyl group viareaction with the appropriate bis(trialkyltin). The reaction isperformed in a suitable inert solvent, for example tetrahydrofuran, inthe presence of a suitable organometallic catalyst, for exampletetrakis(triphenylphosphine). The reaction is performed at a temperatureof 0° C. to 150° C., preferably at 20° C. to 100° C.

Compounds of formula VIII wherein M is B(OH)₂ or a trialkylstannyl groupmay be prepared from compounds of formula X by reaction with a suitablecompound of formula XIII, wherein L is a suitable leaving group M isB(OH)₂ or a trialkylstannyl group, using a suitable acylation procedure.Suitable leaving groups L include: OH, halogen, Oalkyl, Oaryl, OCOalkyl,OCOaryl. A suitable acylation procedure involves treatment of a compoundof formula X with a compound of formula XIII at 0-120° C. in a suitablesolvent. The presence of a base, or, when L=OH, a coupling agent, mayalso be necessary for the reaction to occur. Suitable bases for thereaction include: 4-(N,N-dimethylamino)pyridine, pyridine,triethylamine, N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for examplebenzotriazol-1-yloxytris(dimethylamino)phosphoniurn hexafluorophosphateor benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate;and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula XI may be prepared from compounds of formula XIIwherein J is a halogen or OSO₂CF₃ substituent at the position of ringAr¹ at which the bond to ring Ar² is formed, by reaction with anappropriate organometallic compound of formula VII in the presence of asuitable organometallic catalyst and solvent. Suitable compounds offormula VII include boronic acids, in which M is B(OH)₂ and organotincompounds, in which M is a suitable trialkylstannyl group, for exampletrimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium (0) complexes, for exampletetrakis(triphenylphosphine)palladium (0) or a combination oftris(dibenzylidieneacetone)dipalladium (0) and a suitabletriarylphosphine or triarylarsine ligand, for exampletriphenylphosphine, tri(o-tolyl)phosphine or triphenylarsine. Suitablesolvents include inert ether solvents, for example 1,2-dimethoxyethane,tetrahydrofuran, or 1,4-dioxane, or alcohols, such as ethanol, ormixtures thereof. If the compound of formula VII is a boronic acid, thepresence of a suitable base in addition to the other reagents ispreferred. Suitable bases include sodium carbonate, cesium carbonate,and barium hydroxide. The reaction is carried out at a temperature of0-120° C., and preferably at a temperature of 60-120° C.

Compounds of formula XI may also be prepared from organometalliccompounds of formula XIII by reaction with a compound of formula IX inwhich J is a halogen or OSO₂CF₃ in the presence of a suitableorganometallic catalyst and solvent. Suitable compounds of formula XIIIinclude boronic acids, in which M is B(OH)₂ and organotin compounds, inwhich M is a suitable trialkylstannyl group, for exampletrimethylstannyl or tri-n-butylstannyl. Suitable organometalliccatalysts include palladium (0) complexes, for exampletetrakis(triphenylphosphine)palladium (0) or a combination oftris(dibenzylideneacetone)dipalladium (0) and a suitabletriarylphosphine or triarylarsine ligand, for exampletriphenylphosphine, tri(o-tolyl)phosphine or triphenylarsine. Suitablesolvents include inert ether solvents, for example 1,2-dimethoxyethane,tetrahydrofuran, or 1,4-dioxane, or alcohols, such as ethanol, ormixtures thereof. If the compound of formula VIII is a boronic acid, thepresence of a suitable base in addition to the other reagents ispreferred. Suitable bases include sodium carbonate, cesium carbonate,and barium hydroxide. The reaction is carried out at a temperature of0-120° C., and preferably at a temperature of 60-120° C.

Compounds of formula VII and compounds of formula XIII are eithercommercially available, or may be prepared by methods known to oneskilled in the art. In particular, methods are known to one skilled inthe art for the conversion of aryl halides or heteroaryl halides to arylor heteroaryl boronic acids or aryl or heteroaryl trialkylstannanes,providing methods for the conversion of compounds of formula IX in whichJ is halogen to compounds of formula VII and compounds of formula XII inwhich J is halogen to compounds of formula XIII. For example, boronicacids may be synthesized from aryl or heteroaryl halides via conversionto the aryllithium or arylmagnesium compounds followed by reaction withtrimethylborate, or via reaction with bis(pinacolato)diboron and anorganometallic catalyst, followed by hydrolysis of the resulting borateester (see, for example, Organic Syntheses, 1963, Coll. Vol. 4, 68; J.Org. Chem. 1995, 60, 7508). Trialkylstannanes may be synthesized fromaryl or heteroaryl halides via conversion to the aryllithium orarylmagnesium compounds followed by reaction with the appropriatechlorotrialkyltin, or via reaction with the appropriate bis(trialkyltin)and an organometallic catalyst.

The compounds of formula I in which E is oxygen, sulfur, or NR³ may beprepared according to the methods outlined in Scheme 2.

Compounds of formula I wherein D is oxygen and E is NR³ may be preparedfrom compounds of formula VI wherein J is a halogen or OSO₂CF₃substituent at the position of ring Ar¹ at which the bond to nitrogen isformed, by reaction with an appropriate amine of formula XIV in which EHis NHR³. The reaction may be performed by heating in an inert solvent inthe presence of a suitable strong base. Suitable inert solvents includeether solvents, for example tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, or di(2-methoxyethyl)ether, a hydrocarbon solvent,for example benzene or toluene, or an amide solvent, for exampledimethylformamide, or N-methyl-2-pyrrolidinone. The preferred solvent istetrahydrofuran. Suitable strong bases include alkali metal alkoxide oramide bases, for example sodium t-butoxide or potassium t-butoxide,lithium bis(trimethylsilyl)amide, or lithium diisopropylamide. Thepreferred strong base is sodium t-butoxide. The reaction may require,and is preferably performed in, the presence of an organometalliccatalyst. Suitable organometallic catalysts include complexes ofpalladium (0) with a suitable phosphine ligand, preferably atriarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesized bythe combination of a suitable source of palladium (0), for exampletris(dibenzylideneacetone)dipalladium (0), with the phosphine ligand,and may either be pre-formed or formed in situ by including thepalladium source and phophine ligand in the reaction mixture. Thereaction is carried out at a temperature of 0-150° C., and preferably ata temperature of 60-120° C.

Compounds of formula I wherein D is oxygen and E is R³ may also beprepared from compounds of formula IX wherein J is a halogen or OSO₂CF₃substituent at the position of ring Ar² at which the bond to nitrogen isformed, by reaction with an appropriate amine of formula XV in which EHis NHR³. The reaction may be performed by heating in an inert solvent inthe presence of a suitable strong base. Suitable inert solvents includeether solvents, for example tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, or di(2-methoxyethyl)ether, a hydrocarbon solvent,for example benzene or toluene, or an amide solvent, for exampledimethylformamide, or N-methyl-2-pyrrolidinone. The preferred solvent istetrahydrofuran. Suitable strong bases include alkali metal alkoxide oramide bases, for example sodium t-butoxide or potassium t-butoxide,lithium bis(trimethylsilyl)amide, or lithium diisopropylamide. Thepreferred strong base is sodium t-butoxide. The reaction may require,and is preferably performed in, the presence of an organometalliccatalyst. Suitable organometallic catalysts include complexes ofpalladium (0) with a suitable phosphine ligand, preferably atriarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesized bythe combination of a suitable source of palladium (0), for exampletris(dibenzylideneacetone)dipalladium (0), with the phosphine ligand,and may either be pre-formed or formed in situ by including thepalladium source and phophine ligand in the reaction mixture. Thereaction is carried out at a temperature of 0-150° C., and preferably ata temperature of 60-120° C.

Compounds of formula I wherein D is oxygen and E is oxygen or sulfur maybe prepared from compounds of formula VI wherein J is a halogen orOSO₂CF₃ substituent at the position of ring Ar¹ at which the bond tooxygen is formed, by reaction with an appropriate compound of formulaXIV in which EH is OH or SH. The reaction may be performed by heating inan inert solvent in the presence of a suitable base. The reaction mayrequire, and is preferably performed in, the presence of a catalyst.Suitable inert solvents include ether solvents, for exampletetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ordi(2-methoxyethyl)ether, an amide solvent, for exampledimethylformamide, or N-methyl-2-pyrrolidinone, or a basic heterocyclicaromatic solvent, for example pyridine. The preferred solvent ispyridine. Suitable bases include alkali metal alkoxides, or alkali metalcarbonates, for example potassium carbonate. Suitable organometalliccatalysts include copper or its salts, preferably copper (I) salts, andmost preferably copper (I) iodide. The reaction is carried out at atemperature of 0-150° C., and preferably at a temperature of 100-150° C.

Compounds of formula I wherein D is oxygen and E is oxygen or sulfur mayalso be prepared from compounds of formula IX wherein J is a halogen orOSO₂CF₃ substituent at the position of ring Ar² at which the bond tonitrogen is formed, by reaction with an appropriate compound of formulaXV in which EH is OH or SH. The reaction may be performed by heating inan inert solvent in the presence of a suitable base. The reaction mayrequire, and is preferably performed in, the presence of a catalyst.Suitable inert solvents include ether solvents, for exampletetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ordi(2-methoxyethyl)ether, an amide solvent, for exampleN,N-dimethylformamide, or N-methylpyrrolidinone, or a basic heterocyclicaromatic solvent, for example pyridine. The preferred solvent ispyridine. Suitable bases include alkali metal alkoxides, or alkali metalcarbonates, for example potassium carbonate. Suitable organometalliccatalysts include copper or its salts, preferably copper (I) salts, andmost preferably copper (I) iodide. The reaction is carried out at atemperature of 0-150° C., and preferably at a temperature of 100-150° C.

Compounds of formula I wherein D is oxygen and E is oxygen, sulfur, orNR³ may also be prepared from compounds of formula X by reaction with asuitable compound of formula XVI, wherein E is oxygen, sulfur, or NR³and L is a suitable leaving group, using a suitable acylation procedure.Suitable leaving groups L include: OH, halogen, Oalkyl, Oaryl, OCOalkyl,OCOaryl. A suitable acylation procedure involves treatment of a compoundof formula X with a compound of formula XI at 0-120° C. in a suitablesolvent. The presence of a base, or, when Y=OH, a coupling agent, mayalso be necessary for the reaction to occur. Suitable bases for thereaction include: 4-(N,N-dimethylamino)pyridine, pyridine,triethylamine, N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniurnreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula XV wherein EH is OH, SH, or NHR³ may be preparedfrom compounds of formula X by reaction with a suitable compound offormula XVII, wherein L is a suitable leaving group and EH is OH, SH orNHR³, using a suitable acylation procedure. Suitable leaving groups Linclude: OH, halogen, Oalkyl, Oaryl, OCOalkyl, OCOaryl. A suitableacylation procedure involves treatment of a compound of formula X with acompound of formula XVII at 0-120° C. in a suitable solvent. Thepresence of a base, or, when L=OH, a coupling agent, may also benecessary for the reaction to occur. Suitable bases for the reactioninclude: 4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when L=OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula I, XIV, XV or XVII in which E is NR³ and R³ is analkyl group may be prepared from compounds of the corresponding formulawherein R³ is hydrogen by a suitable alkylation procedure. Typicalalkylation procedures include treatment with an appropriate alkyl halideor sulfonate ester and base, for example sodium hydride, in a suitablesolvent, for example N,N-dimethylformamide, or reductive alkylationusing the appropriate aldehyde or ketone together with a suitablereducing agent in the presence of an acidic catalyst and in an inertsolvent. The preferred method is reductive alkylation. Suitable reducingagents include sodium borohydride and sodium cyanoborohydride. Thepreferred reducing agent is sodium borohydride. Suitable inert solventsinclude water, methanol or ethanol. The preferred solvent is methanol.Suitable acidic catalysts include acetic acid or zinc chloride. Thepreferred acidic catalyst is acetic acid. The reaction is usuallyconducted at a temperature of 0-100° C., and preferably at 20-65° C.

Compounds of formula I, XIV, XV or XVII in which E is NR³ and R³ is anaryl or heteroaryl group may be prepared from compounds of thecorresponding formula wherein R³ is hydrogen by reaction with anappropriate aromatic or heteroaromatic halide ortrifluoromethanesulfonate. The reaction may be performed by heating inan inert solvent in the presence of a suitable strong base. Suitableinert solvents include ether solvents, for example tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or di(2-methoxyethyl)ether, ahydrocarbon solvent, for example benzene or toluene, or an amidesolvent, for example N,N-dimethylformamide, or N-methyl-2-pyrrolidinone.The preferred solvent is tetrahydrofuran. Suitable strong bases includealkali metal alkoxide or amide bases, for example sodium t-butoxide orpotassium t-butoxide, lithium bis(trimethylsilyl)amide, or lithiumdiisopropylamide. The preferred strong base is sodium t-butoxide. Thereaction may require, and is preferably performed in, the presence of anorganometallic catalyst. Suitable organometallic catalysts includecomplexes of palladium (0) with a suitable phosphine ligand, preferablya triarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesized bythe combination of a suitable source of palladium (0), for exampletris(dibenzylidieneacetone)dipalladium (0), with the phosphine ligand,and may either be preformed or formed in situ by including the palladiumsource and phophine ligand in the reaction mixture. The reaction iscarried out at a temperature of 0-150° C., and preferably at atemperature of 60-120° C.

Compounds of formula I in which D is sulfur and E is oxygen or NR¹ maybe prepared from compounds of formula I in which D is oxygen and E isoxygen, or NR³ by reaction with a suitable sulfide in a suitablesolvent. The preferred sulfides are phosphorus sulfides, in particular4-methoxyphenylthionophosphine sulfide dimer (“Lawesson's Reagent”), anddiphosphorus pentasulfide. Suitable solvents for the reaction includearyl hydrocarbon solvents, for example toluene or xylene. The reactionis performed at a temperature of 0-200° C., and preferably at atemperature of 50-180° C.

Compounds of formula XVI wherein D is oxygen and E is NR³ may beprepared from compounds of formula XII wherein J is a halogen or OSO₂CF₃substituent at the position of ring Ar¹ at which the bond to nitrogen isformed, by reaction with an appropriate amine of formula XIV in which EHis NHR³, or, alternatively, from compounds of formula XVII in which EHis NHR³ by reaction with an appropriate compound of formula IX wherein Jis a halogen or OSO₂CF₃ substituent at the position of ring Ar² at whichthe bond to nitrogen is formed. The reaction may be performed by heatingin an inert solvent in the presence of a suitable strong base. Suitableinert solvents include ether solvents, for example tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or di(2-methoxyethyl)ether, ahydrocarbon solvent, for example benzene or toluene, or an amidesolvent, for example N,N-dimethylformamide, or N-methyl-2-pyrrolidinone.The preferred solvent is tetrahydrofuran. Suitable strong bases includealkali metal alkoxide or amide bases, for example sodium t-butoxide orpotassium t-butoxide, lithium bis(trimethylsilyl)amide, or lithiumdiisopropylamide. The preferred strong base is sodium t-butoxide. Thereaction may require, and is preferably performed in, the presence of anorganometallic catalyst. Suitable organometallic catalysts includecomplexes of palladium (0) with a suitable phosphine ligand, preferablya triarylphosphine ligand, and most preferably a bidentatetriarylphosphine ligand. Preferred ligands include2,2′-bis(diphenylphosphino)-1,1′-binaphthyl or1,1′-bis(diphenylphosphino)ferrocene. The catalyst may be synthesized bythe combination of a suitable source of palladium (0), for exampletris(dibenzylideneacetone)dipalladium (0), with the phosphine ligand,and may either be pre-formed or formed in situ by including thepalladium source and phophine ligand in the reaction mixture. Thereaction is carried out at a temperature of 0-150° C., and preferably ata temperature of 60-120° C.

Compounds of formula XVI wherein D is oxygen and E is oxygen or sulfurmay be prepared from compounds of formula XII wherein J is a halogen orOSO₂CF₃ substituent at the position of ring Ar¹ at which the bond tooxygen or sulfur is formed, by reaction with an appropriate compound offormula X[V in which EH is OH or SH, or, alternatively, from compoundsof formula XVII in which EH is OH or SH by reaction with an appropriatecompound of formula IX wherein J is a halogen or OSO₂CF, substituent atthe position of ring Ar² at which the bond to oxygen or sulfur isformed. The reaction may be performed by heating in an inert solvent inthe presence of a suitable base. The reaction may require, and ispreferably performed in, the presence of a catalyst. Suitable inertsolvents include ether solvents, for example tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, or di(2-methoxyethyl)ether, an amidesolvent, for example N,N-dimethylformamide, or N-methyl-2-pyrrolidinone,or a basic heterocyclic aromatic solvent, for example pyridine. Thepreferred solvent is pyridine. Suitable bases include alkali metalalkoxides, or alkali metal carbonates, for example potassium carbonate.Suitable organometallic catalysts include copper or its salts,preferably copper (I) salts, and most preferably copper (I) iodide. Thereaction is carried out at a temperature of 0-150° C., and preferably ata temperature of 100-150° C.

Compounds of formula IX, X and XII, XIV, and XVII are eithercommercially available, known in the literature, or may be prepared bymethods known to one skilled in the art. In particular, a compound offormula X in which A is a moiety of formula II:

may be prepared by the methods described in: J. Gen. Chem. USSR, 1964,2222-2228, U.S. Pat. No. 4,895,543, or EP215650.

It will be appreciated by one skilled in the art that certain optionalaromatic substituents in the compounds of the invention may beintroduced by employing aromatic substitution reactions, or functionalgroup transformations to modify an existing substituent, or acombination thereof. Such reactions may be effected either prior to orimmediately following the processes mentioned above, and are included aspart of the process aspect of the invention. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic functionalisation of an aromatic ring, for example vianitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example via reduction, such as by catalytichydrogenation; acylation, alkylation, sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup via conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group, for example vianucleophilic or organometallically-catalysed substitution reactions.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

The above described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere).

Unless otherwise stated, the above described reactions are conductedunder an inert atmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, Maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallisation, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemisation.

Intermediates

A further aspect of the invention relates to novel intermediates.Intermediates of interest are compounds of formula VI in Scheme 1. Theseintermediates are useful in the synthesis of compounds of formula I, buttheir use is not limited to the synthesis of such compounds.

Accordingly, there is also provided a compound of formula VI:

wherein:

-   -   Ar¹ is a benzene, furan, or thiophene ring;    -   J is halogen, or OSO₂CF₃, provided that when Ar¹ is a benzene        ring, J may only represent halogen or OSO₂CF₃ in a position meta        or para to the carboxamide group; or an enantiomer thereof or        pharmaceutically-acceptable salts thereof.

Particular compounds of this aspect of the invention include:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-bromophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-bromophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-iodophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-iodophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-bromothiophen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-3-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone, and-   (1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;    or enantiomers thereof, or pharmaceutically-acceptable salts    thereof.

Intermediate compounds can exist in enantiomeric forms and may be usedas purified enantiomers, racemates or mixtures.

EXAMPLE 1 (Biphenyl-3-yl)(1,4-diazabicyclo[3.1.2]non-4-yl)methanone

Biphenyl-3-carboxylic acid (52 mg, 0.25 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (50 mg, 0.25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0.25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (81mg, 0.25 mL) and diisopropylethylamine (0.17 mL, 125 mg, 1.0 mmol) indry N,N-dimethylformamide (2 mL) were stirred at ambient temperature for20 h. The reaction mixture was poured into 1N sodium hydroxide solutionand extracted with ethyl acetate (2×). The ethyl acetate layers werecombined and washed with water (2×). The solvent was blown off with astream of nitrogen to yield(biphenyl-3-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone (62 mg, 77%)as a yellow oil. MS (APCI+) 313 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ7.76-7.61 (4H, m), 7.56-7.33 (5H, m), 4.61-4.53 (1H, m), 3.90-3.73 (1H,m), 3.52-3.43 (1H, m), 3.01-2.78 (6H, m), 2.11-1.59 (4H, m).

EXAMPLE 2 (1,4-Diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone

5-Phenylfuran-2-carboxylic acid (49 mg, 0.25 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (50 mg, 0.25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0.25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (81mg, 0.25 mL) and diisopropylethylamine (0.17 mL, 125 mg, 1,0 mmol) indry N,N-dimethylformamide (2 mL) were stirred at ambient temperature for20 h. The reaction mixture was poured into 1N sodium hydroxide solutionand extracted with ethyl acetate (2×). The ethyl acetate layers werecombined and washed with water (2×). The solvent was blown off with astream of nitrogen to yield(1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone (26 mg,34°/O) as a yellow oil. MS (APCI+) 297 [M+1]+. ¹H-NMR (300 MHz, CDCl₃):δ 7.81-7.70 (2H, m), 7.52-7.41 (2H, m), 7.40-7.30 (1H, m), 7.12-7.01(2H, m), 4.59-4.45 (1H, m), 4.01-3.68 (2H, m), 3.04-2.81 (6H, m),2.09-1.60 (4H, m).

EXAMPLE 3(1,4-Diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophene-2-yl)methanone

5-Phenylthiophene-2-carboxylic acid (103 mg, 0.50 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL, 250 mg, 2.0 mmol)in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperaturefor 20 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate (2×). The ethyl acetate layerswere combined and washed with water (2×). The solvent was blown off witha stream of nitrogen to yield(1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophene-2-yl)methanone (122mg, 78%) as a tan oil. MS (APCI+) 313 [M+1]+. ¹H-NM (300 MHz, CDCl₃): δ7.74-7.66 (2H, m), 7.53-7.32 (5H, m), 4.53-4.39 (1H, m), 3.89-3.72 (2H,m), 3.01-2.83 (6H, m), 2.06-1.85 (2H, m), 1.82-1.64 (2H, m).

EXAMPLE 4(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-pyridin-2-yl-thiophen-2-yl)-methanone

5-(2-Pyridyl)thiophene-2-carboxylic acid (42 mg, 0.25 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (50 mg, 0.25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0.25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate.(81 mg, 0.25 mmol) and diisopropylethylamine (0.17 mL, 129 mg, 1.0 mmol)in dry N,N-dimethylformamide (1.5 mL) were stirred at ambienttemperature for 24 h. The reaction mixture was poured into 1N sodiumhydroxide solution and extracted with ethyl acetate. The ethyl acetatelayer was washed with 1N NaOH (1×), water (4×), brine (1×), and driedover Na₂SO₄. After filtration, the solvent was removed in vacuo to yield41 mg of product. The reaction mixture was chromatographed with 100%EtOAc to 90:10 EtOAc:7N NH₃/MeOH to give(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(5-pyridin-2-yl-thiophen-2-yl)-methanone(40 mg, 51%) as a colorless oil. MS (APCI+) 314 [M+1]+; ¹H-NMR (300 MHz,CDCl₃): δ 8.58 (1H, d), 7.77-7.65 (2H, m), 7.50 (1H, d), 7.33 (1H, d),7.21-7.17 (1H, m), 4.68 (1H, s), 3.90 (2H, t), 3.16-2.98 (6H, m),2.10-2.04 (2H, m), 1.91 (1H, s), 1.86-1.75 (2H, m).

EXAMPLE 5(1,4-Diaza-bicyclo[3.2.2]non-4-yl](5-pyridin-3-yl-thiophen-2-yl)-methanone

5-Bromothiophene-2-carboxylic acid (104 mg, 0.502 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.502 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.502 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.502 mmol) and diisopropylethylamine (0.350 mL, 260 mg, 2.01mmol) in dry N,N-dimethylformamide (3.0 mL) were stirred at ambienttemperature for 24 h. The reaction mixture was poured into 1N sodiumhydroxide solution and extracted with ethyl acetate. The ethyl acetatelayer was washed with 1N NaOH (1×), water (4×), brine (1×), and driedover Na₂SO₄. After filtration, the solvent was removed in vacuo to yield(5-Bromo-thiophen-2-yl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone(123 mg, 78%). The product was taken directly into the next reactionwithout any purification.

A conical microwave vessel was charged with(5-bromo-thiophen-2-yl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone(123 mg, 0.390 mmol), 3-pyridylboronic acid (58 mg, 0.468 mmol),dichlorobis(triphenylphosphine)-palladium (II) (2.7 mg, 0.0039 mmol),cesium carbonate (152 mg, 0.468 mmol) and 7:3:2 DME/H₂O/EtOH (2.5 mL).The reaction was run in the Smith Synthesizer at 160° C. for 150seconds. The reaction mixture was filtered through a pad of diatomaceousearth and washed with EtOAc (3×). The combined ethyl acetate layers werewashed with H₂O, dried over Na₂SO₄, filtered and concentrated to give 62mg of product. The mixture was chromatographed with 100% EtOAc to 90:10EtOAc: 7N NH₃/MeOH to give(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(5-pyridin-3-yl-thiophen-2-yl)-methanone(28 mg, 23%) as a white solid. MS (APCI+) 314 [M+1]+; ¹H-NMR (300 MHz,CDCl₃): δ 8.81 (1H, d), 8.49 (1H, dd), 8.05-7.78 (1H, m), 7.28-7.21 (3H,m), 4.58 (1H, s), 3.85-3.76 (2H, m), 3.09-2.91 (6H, m), 2.03-2.01 (2H,m), 1.80-1.69 (2H, m).

EXAMPLE 6(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(3-thiophen-2-yl-phenyl)-methanone

3-Bromobenzoic acid (101 mg, 0.502 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (100 mg, 0.502 mmol), 1-hydroxybenzotriazole hydrate (68mg, 0.502 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (161 mg, 0.502 mmol) and diisopropylethylamine (0.350mL, 260 mg, 2.01 mmol) in dry N,N-dimethylformamide (3.0 mL) werestirred at ambient temperature for 24 h. The reaction mixture was pouredinto 1N sodium hydroxide solution and extracted with ethyl acetate. Theethyl acetate layer was washed with 1N NaOH (1×), water (4×), brine(1×), and dried over Na₂SO₄. After filtration, the solvent was removedin vacuo to yield(3-bromo-phenyl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone (108 mg,70%). The product was taken directly into the next reaction without anypurification.

A conical microwave vessel was charged with(3-Bromo-phenyl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone (108 mg,0.349 mmol), 2-thiopheneboronic acid (54 mg, 0.419 mmol),dichlorobis(triphenylphosphine)-palladium (II) (2.4 mg, 0.00349 mmol),cesium carbonate (137 mg, 0.419 mmol) and 7:3:2 DME/H₂O/EtOH (2.5 mL).The reaction was run in the Smith Synthesizer at 160° C. for 150seconds. The reaction mixture was filtered through a pad of diatomaceousearth and washed with EtOAc (3×). The combined ethyl acetate layers werewashed with H₂O, dried over Na₂SO₄, filtered and concentrated to give 98mg of product. The mixture prepared on the Gilson reverse phase HPLC togive(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(3-thiophen-2-yl-phenyl)-methanone(90 mg, 83%) as a colorless oil, TFA salt. MS (APCI+) 313 [M+1]+; ¹H-NMR(300 MHz, CDCl₃): δ 12.04 (1H, s), 7.72 (1H, d), 7.62 (1H, s), 7.47 (1H,t), 7.35-7.29 (3H, m), 7.11 (1H, t), 5.05 (1H, s), 3.93 (2H, s),3.55-3.52 (6H, m), 2.39 (2H, s), 2.20 (2H, s).

EXAMPLE 7(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(5-thiophen-2-yl-furan-2-yl)-methanone

5-Bromo-2-furoic acid (96 mg, 0.502 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.502 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.502 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.502 mmol) and diisopropylethylamine (0.350 mL, 260 mg, 2.01mmol) in dry N,N-dimethylformamide (3.0 mL) were stirred at ambienttemperature for 24 h. The reaction mixture was poured into 1N sodiumhydroxide solution and extracted with ethyl acetate. The ethyl acetatelayer was washed with 1N NaOH (1×), water (4×), brine (1×), and driedover Na₂SO₄. After filtration, the solvent was removed in vacuo to yield(5-bromo-furan-2-yl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone (84mg, 56%). The product was taken directly into the next reaction withoutany purification.

A conical microwave vessel was charged with(5-bromo-furan-2-yl)-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-methanone (84mg, 0.281 mmol), 2-thiopheneboronic acid (43 mg, 0.337 mmol),dichlorobis(triphenylphosphine)-palladium (II) (2.0 mg, 0.00281 mmol),cesium carbonate (110 mg, 0.337 mmol) and 7:3:2 DME/H₂O/EtOH (2.5 mL).The reaction was run in the Smith Synthesizer at 160° C. for 150seconds. The reaction mixture was filtered through a pad of diatomaceousearth and washed with EtOAc (3×). The combined ethyl acetate layers werewashed with H₂O, dried over Na₂SO₄, filtered and concentrated to give 70mg of product. The mixture prepared on the Gilson reverse phase HPLC togive(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(5-thiophen-2-yl-furan-2-yl)-methanone(33 mg, 39%) as a colorless oil, TFA salt. MS (APCI+) 303 [M+1]+; ¹H-NMR(300 MHz, CDCl₃): δ 12.55 (1H, s), 7.35 (2H, t), 7.11 (1H, dd), 6.50(1H, d), 6.54 (1H, s), 5.03-5.01 (1H, m), 4.27 (2H, s), 3.69-3.47 (6H,m), 2.46 (2H, s), 2.29-2.26 (2H, m).

EXAMPLE 8[5-(4-Chlorophenyl)furan-2-yl](1,4-diaza-bicyclo[3.2.2]non-4-yl)methanone

5-(4-Chlorophenyl)furan-2-carboxylic acid (56 mg, 0.25 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (50 mg, 0.25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0.25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate(81 mg, 0.25 mL) and diisopropylethylamine (0.17 mL, 125 mg, 1.0 mmol)in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperaturefor 42 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with 1N NaOH (1×), water (4×), brine (1×) and dried over Na₂SO₄.The solvent was removed in vacuo to yield[5-(4-chlorophenyl)furan-2-yl](1,4-diaza-bicyclo[3.2.2]non-4-yl)methanone(76 mg, 92%) as a beige semisolid. MS (APCI+) 331/333 [M+1]+. ¹H-NMR(300 MHz, CDCl₃): δ 7.83-7.74 (2H, d), 7.58-7.49 (2H, d), 7.18-7.11 (1H,m), 7.11-7.04 (1H, m), 4.55-4.46 (1H, m), 3.97-3.68 (2H, m), 3.04-2.84(6H, m), 2.09-1.89 (2H, m), 1.89-1.61 (2H, m).

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically-acceptable salt thereof, effective in treating orpreventing such disorder or condition in admixture with an inertpharmaceutically-acceptable diluent or carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I, or an enantiomer thereof, orpharmaceutically-acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inertpharmaceutically-acceptable diluent or carrier.

Examples of diluents and carriers are:

-   -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   for capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically-acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the diseases or conditions mentioned herein; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically-acceptable salt thereof, to apatient.

Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α₇ nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α₄ nAChRsubtype. Therefore, compounds which are selective for the α₇ nAChRsubtype are preferred. The compounds of the invention are indicated aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania and manic depression,and anxiety. Examples of intellectual impairment disorders includeAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, Lewy Body Dementia, memory loss, and Attention DeficitHyperactivity Disorder. The compounds of the invention may also beuseful as analgesics in the treatment of pain (including chronic pain)and in the treatment or prophylaxis of Parkinson's disease, Huntington'sdisease, Tourette's syndrome, and neurodegenerative disorders in whichthere is loss of cholinergic synapses. The compounds may further beindicated for the treatment or prophylaxis of jetlag, for use ininducing the cessation of smoking, and for the treatment or prophylaxisof nicotine addiction (including that resulting from exposure toproducts containing nicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis and irritablebowel disease.

Pharmacology

The pharmacological activity of the compounds of the invention may bemeasured in the tests set out below:

Test A—Assay for Affinity at α₇ nAChR Subtype

¹²⁵I-α-Bungarotoxin (BTX) Binding to Rat Hippocampal Membranes.

Rat hippocampi were homogenized in 20 volumes of cold homogenisationbuffer (HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000×g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000×g, washed, and re-suspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pre-treating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Non-specific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the a 4 nAChR Subtype

[³H]-(−)-Nicotine Binding.

Using a procedure modified from Martino-Barrows and Kellar (Mol Pharm(1987) 31:169-174), rat brain (cortex and hippocampus) was homogenisedas in the [¹²⁵I]α-BTX binding assay, centrifuged for 20 minutes at12,000×g, washed twice, and then re-suspended in HB containing 100 μMdiisopropyl fluorophosphate. After 20 minutes at 4° C., membranes(approximately 0.5 mg) were incubated with 3 nM [³H]-(−)-nicotine, testdrug, 1 μM atropine, and either 2 mM CaCl₂ or 0.5 mM EGTA for 1 hour at4° C., and then filtered over Whatman glass fibre filters (thickness C)(pre-treated for 1 hour with 0.5% PEI) using a Brandel cell harvester.Non-specific binding was described by 100 μM carbachol, and specificbinding was typically 84%.

Binding Data Analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (n_(H)) were calculated usingthe non-linear curve fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding K_(D) values of 1.67and 1.70 nM for the ¹²⁵I-α-BTX and [³H]-(−)-nicotine ligandsrespectively. K_(i) values were estimated using the generalCheng-Prusoff equation:K _(i) =[IC ₅₀/((2+([ligand]/K _(D)])^(n))^(1/n)−1)

-   -   where a value of n=1 was used whenever n_(H)<1.5 and a value of        n=2 was used when n_(H)≧1.5. Samples were assayed in triplicate        and were typically ±5%. K_(i) values were determined using 6 or        more drug concentrations. The compounds of the invention are        compounds with binding affinities (K_(i)) of less than 10 μM in        either Test A or Test B, indicating that they are expected to        have useful therapeutic activity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

1. A compound of formula I:

wherein: A is a moiety of formula II:

D is oxygen or sulfur; E is a single bond, oxygen, sulfur, or NR³; Ar¹is a 5- or 6-membered aromatic heterocyclic ring having 1, 2 or 3heteroatoms selected from nitrogen, oxygen or sulfur where not more thanone of said heteroatoms is oxygen or sulfur, or Ar¹ is phenyl; Ar² is a5- or 6-membered aromatic heterocyclic ring having 1, 2 or 3 heteroatomsselected from nitrogen, oxygen or sulfur where not more than one of saidheteroatoms is oxygen or sulfur, or Ar² is phenyl, or Ar² is an 8- or9-, or 10-membered fused aromatic carbocyclic ring or fused aromaticheterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur where not more than one of said heteroatoms is oxygenor sulfur, or an 8- or 9-, or 10-membered aromatic carbocyclic ring; therings Ar¹ and Ar² are substituted with 0, 1, 2 or 3 substituentsselected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂,CF₃NR¹R², CH₂NR¹R², OR², CH₂OR² or CO₂R³; R¹ and R² at each occurrenceare independently selected from hydrogen, C₁₋₄alkyl, aryl, heteroaryl,C(O)R³, C(O)NHR³, CO₂R³ or SO₂R³, or R¹ and R² in combination is—(CH₂)_(j)G(CH₂)_(k)— wherein G is oxygen, sulfur, NR³, or a bond; a, band c are each 1 or 2; j is 2, 3 or 4; k is 0, 1 or 2, and R³ at eachoccurrence is independently selected from hydrogen, C₁₋₄alkyl, aryl, orheteroaryl; or a diastereoisomer, enantiomer orpharmaceutically-acceptable salt thereof.
 2. A compound according toclaim 1, wherein D is oxygen.
 3. A compound according to claim 2,wherein E is a single bond.
 4. A compound according to claim 2, whereinE is oxygen or NR³.
 5. A compound according to claim 1, wherein A is

or a diastereoisomer, enantiomer or pharmaceutically-acceptable saltthereof.
 6. A compound of claim 1, wherein Ar¹ is a 5- or 6-memberedaromatic heterocyclic ring having 1 or 2 heteroatoms selected fromnitrogen, oxygen or sulfur where not more than one of said heteroatomsis oxygen or sulfur, or Ar¹ is phenyl, or a diastereoisomer, enantiomeror pharmaceutically-acceptable salt thereof.
 7. A compound according toclaim 6 wherein Ar¹ is a benzene ring, furan ring or thiophene ring. 8.A compound according to claim 1, wherein Ar² is a 5- or 6-memberedaromatic heterocyclic ring having 1 or 2 heteroatoms selected fromnitrogen, oxygen or sulfur where not more than one of said heteroatomsis oxygen or sulfur, or a phenyl, or a diastereoisomer, enantiomer orpharmaceutically-acceptable salt thereof.
 9. A compound according toclaim 8, wherein Ar² is a benzene ring, furan ring, thiophene ring, orpyridine ring.
 10. A compound according to claim 1, wherein the -EAr²and the C(=D)A moieties on Ar¹ are positioned in a 1,3-relationshiprelative to each other; or a diastereoisomer, enantiomer orpharmaceutically-acceptable salt thereof.
 11. A compound according toclaim 1, wherein Ar¹ or Ar² is substituted with 0 or 1 substituentsselected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, CN, NO₂,NR¹R², CH₂NR¹R², OR³, CH₂OR³, CO₂R³ or CF₃; or a diastereoisomer,enantiomer or pharmaceutically-acceptable salt thereof.
 12. A compoundaccording to claim 1, wherein A is a moiety of formula II:

D is oxygen; E is a single bond; Ar¹ is a 5- or 6-membered aromaticheterocyclic ring having 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur where not more than 1 of said heteroatoms is oxygen orsulfur, or Ar¹ is phenyl Ar² is a 5- or 6-membered aromatic heterocyclicring having 1, 2 or 3 heteroatoms selected from nitrogen, oxygen orsulfur where not more than 1 of said heteroatoms is oxygen or sulfur, orAr² is phenyl, or a diastereoisomer, enantiomer orpharmaceutically-acceptable salt thereof.
 13. A compound of claim 12,wherein Ar¹ is a benzene ring, furan ring or thiophene ring.
 14. Acompound according to claim 1, having the groups -EAr² and —C(═O)A,positioned in a 1,3-relationship relative to each other and wherein Ar²has 0 or 1 substituents selected from: halogen, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, NO₂, NR¹R², CH₂NR¹R², OR¹, CH₂OR¹, CO₂R or CF₃; or adiastereoisomer, enantiomer or pharmaceutically-acceptable salt thereof.15. A compound according to claim 1, selected from:(1,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-3-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(2-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(3-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(4-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-2-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(furan-3-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-2-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-(thiophen-3-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(biphenyl-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylfuran-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(2-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(4-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-2-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-3-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-2-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-3-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-phenylthiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(2-pyridyl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(3-pyridyl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(4-pyridyl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-2-yl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-3-yl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-2-yl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-3-yl)thiophen-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-phenylfuran-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)furan-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(2-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(3-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(4-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-2-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(furan-3-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-2-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-(thiophen-3-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-phenylfuran-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(2-pyridyl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(3-pyridyl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(4-pyridyl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-2-yl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(furan-3-yl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-2-yl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(2-(thiophen-3-yl)furan-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-phenylthiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(2-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(3-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(4-pyridyl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-2-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(furan-3-yl)thiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-2-yl)thiophen-2-yl)methanone,or(1,4-diazabicyclo[3.2.2]non-4-yl)(4-(thiophen-3-yl)thiophen-2-yl)methanone,or a diastereoisomer, enantiomer or pharmaceutically-acceptable saltthereof. 16-18. (canceled)
 19. A method of treatment or prophylaxis ofpsychotic disorders, intellectual impairment disorders, human diseasesor conditions in which activation of the α7 nicotinic receptor isbeneficial, Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, Lewy Body Dementia, Attention DeficitHyperactivity Disorder, anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis which method comprises administering atherapeutically effective amount of a compound as defined in claim 1.20. A pharmaceutical composition comprising a compound of formula I, asdefined in claim 1, together with at least onepharmaceutically-acceptable excipient or diluent.
 21. A process for thepreparation of a compound of formula I, as defined in claim 1, whichcomprises: reacting a compound of formula VI:

wherein J represents halogen, or OSO₂CF₃ substituent at the position ofring Ar¹ at which the bond to ring Ar² is formed with a organometalliccompound of formula VII;Ar²-M  VII in the presence of a organometallic catalyst and solvent. 22.A compound of formula VI:

wherein: Ar¹ is a benzene, furan, or thiophene ring; J is halogen, orOSO₂CF₃, provided that when Ar¹ is a benzene ring, J may only representhalogen or OSO₂CF₃ in a position meta or para to the carboxamide group;or an enantiomer thereof or pharmaceutically-acceptable salts thereof.23. A compound according to claim 22, selected from:(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-bromophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-bromophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-iodophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-iodophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-bromothiophen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromothiophen-3-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone, and(1,4-diazabicyclo[3.2.2]non-4-yl)(5-bromofuran-2-yl)methanone; orenantiomers thereof, or pharmaceutically-acceptable salts thereof.